Phase III pivotal study of defibrotide for hepatic veno-occlusive disease is published in Blood.- Jazz Pharma

Jazz Pharmaceuticals plc announced that data from the phase III pivotal study of defibrotide were published online in BLOOD, the Journal of the American Society of Hematology (ASH). The data demonstrated that defibrotide use in patients with hepatic veno-occlusive (VOD), also known as sinusoidal obstruction syndrome (SOS), with multi-organ failure (MOF) post-hematopoietic stem-cell transplantation (HSCT) was associated with a statistically significant improvement in Day +100 survival and in rate of complete response (CR) by Day +100, compared with rigorously selected historical controls.

Defibrotide is an investigational agent in the United States (U.S.). A new drug application (NDA) is under review by the FDA. Hepatic VOD/SOS can be a life-threatening complication of HSCT. Hepatic VOD/SOS with MOF has been associated with 84% mortality rate. The phase III study investigated the safety and efficacy of defibrotide in adult and pediatric patients with established hepatic VOD/SOS with MOF. Patients (n=102) given 25 mg/kg/day defibrotide were compared with 32 historical controls identified from review of medical charts of HSCT patients by an independent medical review committee, blinded to outcome. Baseline characteristics between groups were well balanced. The historical-control methodology offers a novel approach for phase III evaluation of orphan diseases associated with high mortality, where a placebo control would be unethical. Defibrotide was associated with a statistically significant improvement in Day +100 post-HSCT survival, the primary endpoint, compared to the historical controls. The estimated between-group difference in Day +100 survival was 23.0% (95.1% confidence interval (CI): 5.2%-40.8%; P=.0109), using a propensity-adjusted analysis. The difference of complete response (CR) rates by Day +100 post-HSCT, a secondary endpoint, resulted in an estimated between-group difference adjusted for propensity score of 19.0% (95.1% CI: 3.5 - 34.6; P=.0160). Median duration of treatment with defibrotide was 21.5 days.

Hypotension was the most common adverse event in both groups (39.2% with defibrotide and 50.0% for historical controls). Related adverse events included hemorrhage and hypotension. There was no difference in the incidence of common hemorrhagic events between defibrotide and the historical controls.

Comment: Defibrotide is the first and only licensed treatment of hepatic veno-occlusive disease in HSCT.(hemetopoietic stem cell therapy). Defibrotide was EU approved in 2013 as Defitelio.